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TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans

Bart Ferwerda1, Matthew B B McCall, Santos Alonso

  • 1Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

Proceedings of the National Academy of Sciences of the United States of America
|October 11, 2007
PubMed

Insights

Genetic variations in Toll-like receptor 4 (TLR4) influenced human evolution. Specific TLR4 polymorphisms may have offered protection against malaria in Africa but increased susceptibility to bacterial infections in Eurasia.

Area of Science:

  • Immunology
  • Human Evolutionary Genetics
  • Infectious Disease Epidemiology

Background:

  • Infectious diseases are a significant driver of human evolution, shaping the innate immune system.
  • Polymorphisms in Toll-like receptor 4 (TLR4) are linked to susceptibility to Gram-negative infections and septic shock.

Purpose of the Study:

  • To investigate the evolutionary history and functional implications of TLR4 polymorphisms (Asp299Gly and Thr399Ile) in different human populations.
  • To understand how these genetic variations may have conferred advantages or disadvantages in response to specific infectious disease pressures during human migrations.

Main Methods:

  • Analysis of the population distribution of TLR4 polymorphisms (Asp299Gly and Thr399Ile) across Africa, Asia, and Europe.
  • Genetic and functional studies to evaluate the evolutionary model of TLR4 polymorphism adaptation.

Main Results:

  • The Asp299Gly polymorphism exhibits distinct geographical distributions, with high prevalence in sub-Saharan Africa.
  • Evidence suggests the Asp299Gly allele may have evolved as a protective factor against malaria.
  • This allele might have increased susceptibility to severe bacterial infections in Eurasian populations.
  • The Asp299Gly/Thr399Ile haplotype appears to be selectively neutral.

Conclusions:

  • TLR4 polymorphisms demonstrate how environmental infectious pressures interact with the innate immune system to shape human genetic variation.
  • These findings highlight the role of immune system adaptation during the out-of-Africa migration of modern humans.

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